The Section on Directed Gene Delivery creates viral vectors to efficiently deliver genes to appropriate targets in cellula, at physiological expression stoichiometries, with the end goal of transferring therapeutic genes to cells of the central nervous system for expression at physiological levels to complement impaired physiological function in vivo. Recent advances in human CNS gene therapy to treat deficiencies in AADC and other enzymes have occurred through mobilization of AAV vectors, an effective short-term therapy with however potential limitations for lifetime therapeutic application. Accordingly, we have developed a workflow for the construction of targeted retroviral vectors for delivery to specific cell types in rodent brain, with direct translatability to primate species. The identification of additional retroviral receptors (Xu W, et al. (2013) PNAS 110:11547-11552) has also allowed us to begin construction of transgenic mouse lines expressing humanized retroviral vectors with envelopes replacing the currently used, but somewhat cytotoxic, VSV envelope, also for the purpose of enhancing translation of rodent gene delivery experiments to human CNS gene therapy application. Our most successful application of retroviral packaging for physiological expression this year has come with the development for high-throughput screening and receptor ligand characterization of several cell lines in which G-protein coupled receptors (GPCRs) are co-expressed with a recently-discovered CNS-specific cAMP sensor, NCS/Rapgef2, allowing novel signaling pathways for activation of the MAP kinase ERK, involved in cellular plasticity underlying memory, learning and adaptation to stress, to be elucidated and drugs to activation and inhibiting them to be developed (Emery AC, Eiden MV, Eiden LE (2013). Mol Pharmacol 83:95-105, Emery AC, Eiden MV, Mustafa T, Eiden LE (2013) Sci Signal 6:ra51, Emery AC, Eiden MV, Eiden LE (2014) J Biol Chem 289:10126-39), We have also reported that two aspects of cAMP-induced differentiation, neurite extension and growth arrest, are dissociable at the level of the sensors conveying the cAMP signal in PC12 and NS-1 cells. Following cAMP elevation, neuritogenic cyclic AMP sensor/Rapgef2 is activated for signaling to ERK to mediate neuritogenesis, whereas Epac2 is activated for signaling to the MAP kinase p38 to mediate growth arrest. Furthermore cAMP- and NGF-dependent signaling for differentiation are completely insulated from each other The availability of optimized preclinical vectors for in vivo testing, and cell lines constructed from human GPCRs and other signaling components expressed at appropriate cellular stoichiometry, should continue to be a valuable resource for the national neuroscience community, to serve seamlessly as tools for hypothesis-driven basic research, and again for clinical research, without a need for translational scientists to re-set the gene therapeutic platform for the clinic.